Synthesis of E- and Z-Trisubstituted Alkenes Using Chemoselective Cross-Metathesis

Synthesis of E- and Z-trisubstituted alkenes using chemoselective cross-metathesis. Combination with cross-coupling reactions

Catalytic cross-metathesis is a short and straightforward approach to obtain acyclic trisubstituted alkenes, that are biologically active natural products as well as useful intermediates and precursors for further transformations (such as enantioselective hydrogenations, allylic substitutions, conjugate additions or cross-coupling reactions). However, the lack of chemoselectivity (see later) represents a major limitation of this approach.

Very recently, XiMo founders, Amir H. Hoveyda & Richard R. Schrock, worked out a novel procedure that allows chemoselective access to linear E- or Z-trisubstituted alkenes coupled with exceptional stereoisomeric purity (> 98 % E or > 95 % Z) through cross-metathesis reactions involving E- or Z-trisubstituted alkenes. The starting olefins can be obtained from commercially available starting materials by cross-coupling reactions.  The utility of the strategy is demonstrated in various examples. 

The novelty of their approach is the following: they carry out a cross metathesis reaction between a trisubstituted alkene and a disubstituted alkene instead of applying a monosubstituted and a 1,1-disubstituted alkene having an unsubstituted terminal alkenyl methylene unit. The original approach suffers from the relative instability of methylidene species, and the lack of chemoselectivity, namely, the homometathesis of the terminal olefin is prevalent. On the other hand, trisubstituted olefin precursors make the catalytic cycle more stereoselective compared to the less substituted variant due to the emergence of steric hindrance.  

The following Mo-catalysts (Mo-1Mo-5) were used in the chemoselective synthesis of various trisubstituted alkenes (including E or Z chloro- and bromo-olefins) in high stereoisomeric purity.

The catalyst that is in the article referred as Mo-3 has already been marketed by XiMo in bulk (X643) and in paraffin formulated pellets (XiMoPac-Mo005).

Cross-metathesis synthesis of E or Z chloro-olefins

Cross-metathesis synthesis of E or Z bromo-olefins

The E- or Z-trisubstituted alkenyl halides may be converted to other trisubstituted alkenes while preserving the stereochemistry through subsequent cross-coupling reaction.

Trialkyl substituted olefins could be accessed using Mo-3 catalyst and olefin precursors with high stereoselectivity even if the disubstituted parent olefin was a mixture of E/Z isomers.

The smart combination (or alternated use) of cross-coupling reactions and stereoretentive/ stereoselective cross-metathesis reactions represent a novel synthetic strategy towards various, unique trisubstituted olefins and will find broad applicability.

References:

Nguyen, T. T., Koh, M. J., Mann, T. J., Schrock, R. R., & Hoveyda, A. H. (2017). Synthesis of E-and Z-trisubstituted alkenes by catalytic cross-metathesis. Nature, 552, 347.

You can find further readings for Mo-3 and Mo-4 under “Olefin Metathesis Highlights”.

For the combination of cross metathesis and cross-coupling reactions, see also:

Hoveyda, et al. J. Am. Chem. Soc. 2014, 136, 16136.

Schrock, Hoveyda, et al. J. Am. Chem. Soc, 2013, 135, 6026.

These publications refer to Mo and W catalysts that are marketed by XiMo in bulk (X639, X030) and in paraffin formulated pellets (XiMoPac-W001 and XiMoPac-Mo004).

Information about the stabilized paraffin pellets can be found here: “From Box to Bench: Air-Stable Molybdenum Catalyst Tablets for Everyday Use in Olefin Metathesis”

02. March, 2018

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